THE TRANSCRIPTION FACTOR IRF8 EPIGENETICALLY REGULATES EARLY DENDRITIC CELL SPECIFICATION

Abstract

Dendritic cells (DCs) are vital for immune responses to pathogens. These cells are produced from bone marrow hematopoietic stem cells via common DC progenitors (CDPs). Recently, DC lineage fate decisions occurring at stages much earlier than CDPs have been recognized, yet the mechanism remains unknown. In this study, we demonstrate that IRF8 regulates chromatin at the LMPP stage to induce early commitment towards DCs. Single-cell RNA-seq revealed that the expression of IRF8, a transcription factor essential for DC and monocyte development, was initiated in a subpopulation within LMPPs. By in vivo transfer experiments, we showed that these IRF8 expressing LMPP (IRF8+ LMPPs) were derived from IRF8- LMPPs and predominantly produced DCs, especially classical DC1s (cDC1s). On the other hand, IRF8+ LMPPs did not generate significant numbers of monocytes, neutrophils or lymphocytes. RNA-seq and an assay for transposase-accessible chromatin (ATAC)-seq revealed that IRF8- and IRF8+ LMPPs displayed very similar global gene expression patterns; however, the chromatin of enhancers near DC lineage genes was more accessible in IRF8+ LMPPs than in IRF8- LMPPs, an epigenetic change dependent on IRF8. The majority of the genes epigenetically primed by IRF8 were still transcriptionally inactive at the LMPP stage, but were highly expressed in the downstream DC lineage populations such as CDPs and cDC1s. Therefore, early expression of the key transcription factor IRF8 changes chromatin states in otherwise multipotent progenitors, thereby biasing their fate decision towards DCs.